肝细胞癌
体内
衣壳
乙型肝炎病毒
体外
病毒学
药物发现
抗病毒药物
药理学
病毒复制
肝硬化
丙型肝炎病毒
化学
病毒
医学
生物
癌症研究
内科学
生物化学
生物技术
作者
Leda Ivanova Bencheva,Lorena Donnici,Luca Ferrante,Adolfo Prandi,Roberta Sinisi,Marilenia De Matteo,Pietro Randazzo,Matteo Conti,Pietro Di Lucia,Elisa Bono,Leonardo Giustini,Maria Vittoria Orsale,Alexandros Patsilinakos,Edith Monteagudo,Matteo Iannacone,Vincenzo Summa,Luca G. Guidotti,Raffaele De Francesco,Romano Di Fabio
标识
DOI:10.1016/j.bmcl.2022.128904
摘要
Chronic hepatitis B (CHB) is a major worldwide public health problem and novel anti-HBV therapies preventing liver disease progression to cirrhosis and hepatocellular carcinoma are urgently needed. Over the last several years, capsid assembly modulators (CAM) have emerged as clinically effective anti-HBV agents which can inhibit HBV replication in CHB patients. As part of a drug discovery program aimed at obtaining novel CAM endowed with high in vitro and in vivo antiviral activity, we identified a novel series of sulfamoylbenzamide (SBA) derivatives. Compound 10, one of the most in vitro potent SBA-derived CAM discovered to date, showed excellent pharmacokinetics in mice suitable for oral dosing. When studied in a transgenic mouse model of hepatic HBV replication, it was considerably more potent than NVR 3-778, the first sulfamoylbenzamide (SBA) CAM that entered clinical trials for CHB, at reducing viral replication in a dose-dependent fashion. We present herein the discovery process, the SAR analysis and the pre-clinical profile of this novel SBA CAM.
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